Technological developments in the field of genomics now afford the opportunity to define the complete sequence of an individual's genome in a rapid and affordable manner. Such whole genome sequencing and its simpler corollary, whole exome sequencing (WES), have already established themselves as powerful research tools. The natural next step in the evolution of this technology is its direct application in the clinical arena. However, while such technology holds considerable clinical promise, tremendous challenges exist in applying it and deriving practical benefit to patients. In this proposal we outline a highly interdisciplinary approach to identifying, confronting and overcoming the major challenges which must be met in order to implement deep sequencing technology in clinical medicine. Aim 1 will explore the use of WES as a diagnostic tool in the care of a broad array of patients, evaluate its performance, identify critical clinical characteristics which can guide its application and measure the impact of such information on patients and providers. Aim 2 will tackle one of the most pressing challenges in the clinical application of WES: the inevitable generation of collateral or bystander information. Educational materials will be developed to enable patients to make decisions about appropriate return of results and the impact of collateral information will be assessed at the level of the provider, laboratory and patient. The third major challenge in clinical implementation of genomic medicine, how do deal with vast amounts of information, will be addressed by Aim 3. A clinically oriented binning structure will be created and refined for classifying, storing and transmitting data within practical categories so as to make sense of the large amounts of data generated. Finally, as we stand on the cusp of genomic medicine, we must ensure that all have access to its benefits. Thus, Aim 4 will pursue clinical WES in traditionally underrepresented populations to identify special opportunities and challenges in the clinical translation of this new tool to the broadest possible population. Our ultimate aim is to establish a set of best practices to guide future implementation of robust genomic technologies for the real and practical betterment of human health. PUBLIC HEALTH RELEVANCE: Genomic medicine has tremendous potential to improve human health by facilitating improved diagnosis, offering deep insight into mechanisms of disease and by enabling individually targeted prevention and treatment. In this proposal we will confront the major challenges which stand between genomic medicine and its broad implementation to a diverse population.